A5067112139- Toxin Mechanisms and Immunotoxins
- Silymarin and Mushroom Poisoning
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Cell Adhesion Molecules Research
- Pharmaceutical studies and practices
- Multiple Myeloma Research and Treatments
- Flavonoids in Medical Research
- Urinary and Genital Oncology Studies
- Ion channel regulation and function
- Sarcoma Diagnosis and Treatment
- Nanoparticle-Based Drug Delivery
- Immunotherapy and Immune Responses
- Bladder and Urothelial Cancer Treatments
- Intestinal Malrotation and Obstruction Disorders
- Drug-Induced Adverse Reactions
- Psychiatric care and mental health services
- Peptidase Inhibition and Analysis
- Microbial Natural Products and Biosynthesis
- Cancer Treatment and Pharmacology
- Supramolecular Self-Assembly in Materials
- thermodynamics and calorimetric analyses
- RNA Interference and Gene Delivery
- Pharmacogenetics and Drug Metabolism
- Mass Spectrometry Techniques and Applications
Heidelberg Pharma (Germany)
2014-2021
Max Planck Institut für Zellbiologie
2019
University Medical Center Freiburg
2008-2009
Molina Center for Energy and the Environment
2007
Max-Planck-Institut für Kohlenforschung
2006
Max Planck Society
2006
University of Würzburg
2003
Abstract The MDM2‐antagonist Nutlin 3A can efficiently induce apoptosis in osteosarcoma cell lines with amplified MDM2 . However, Nutlin‐based therapy could be even more important common sarcoma types where this aberration is frequent. well‐ and de‐differentiated liposarcomas have complex marker chromosomes, consistently including multiple copies of the locus. Since amplification seems to a primary these tumors, whereas generally progression marker, underlying biological mechanisms may...
Despite major treatment advances in recent years, patients with multiple myeloma inevitably relapse. The RNA polymerase II complex has been identified as a promising therapeutic target both proliferating and dormant cancer cells. Alpha-amanitin, toxin so far without clinical application due to high liver toxicity, specifically inhibits this complex. Here, we describe the development of HDP-101, an anti-B-cell maturation antigen (BCMA) antibody conjugated amanitin derivative. HDP-101...
Personalized medicine in cancer treatment has the potential to enhance therapeutic efficacy while simultaneously reducing adverse effects. Molecular characterization of circulating tumor cells (CTCs) offers invaluable insight into metastasis tumor...
α-Amanitin and related amatoxins have been studied for more than six decades mostly by isolation from death cap mushrooms. The total synthesis, however, remained challenging due to unique structural features. is a potent inhibitor of RNA polymerase II. Interrupting the basic transcription processes eukaryotes leads apoptosis cell. This mechanism makes toxin an ideal payload antibody-drug conjugates (ADCs). Only microgram quantities toxins, when delivered selectively tumor sites through...
Herein we describe the design and biological evaluation of a novel antitumor therapeutic platform that combines most favorable properties small-molecule drug conjugates (SMDCs) antibody (ADCs). Although small size SMDCs, compared to ADCs, is an appealing feature for their application in treatment solid tumors, SMDCs usually suffer from poor pharmacokinetics, which severely limits efficacy. To overcome this limitation, proof-of-concept study grafted α-amanitin-based SMDC targets prostate...
Abstract A comparative investigation shows that hydroxylated 10‐membered lactones modeled around the fungal metabolites microcarpalide ( 1 ) and pinolidoxin 2 are endowed with selective actin‐binding properties. Although less potent than marine natural product latrunculin A, which represents standard in field, nonenolides of this type significantly toxic accommodate substantial structural editing. Most notable is fact even an intramolecular transesterification formation a butanolide skeleton...
RGD-α-amanitin and isoDGR-α-amanitin conjugates were synthesized by joining integrin ligands to α-amanitin via various linkers spacers. The evaluated for their ability inhibit biotinylated vitronectin binding the purified αVβ3 receptor, retaining good affinity, in same nanomolar range as free ligands. antiproliferative activity of was three cell lines possessing different levels expression: human glioblastoma U87 (αVβ3+), lung carcinoma A549 (αVβ3-) breast adenocarcinoma MDA-MB-468 (αVβ3-)....
A non-internalizing conjugate targeting α<sub>v</sub>β<sub>3</sub> integrin inhibits the proliferation of integrin-expressing cancer cells in presence β-glucuronidase.
Abstract Alpha‐amanitin, an extremely toxic bicyclic octapeptide extracted from the death‐cap mushroom, Amanita phalloides , is a highly selective allosteric inhibitor of RNA polymerase II. Following on growing interest in using this toxin as payload antibody‐drug conjugates, herein we report synthesis and biochemical evaluation several new derivatives to probe role trans ‐hydroxyproline (Hyp), which known be critical for toxicity. This structure activity relationship (SAR) study represents...
Abstract Background: ATACs (antibody-targeted Amanitin conjugates) comprise a new class of antibody-drug conjugates using amanitin as toxic payload. binds to the eukaryotic RNA pol II and thereby inhibits cellular transcription process at very low concentrations. In current study, in vitro vivo data targeting BCMA (B Cell Maturation Antigen, also known CD269) are presented. is selectively expressed on malignant plasma cells like multiple myeloma (MM) hence considered an ideal target for...
Abstract α‐Amanitin und verwandte Amatoxine werden schon über 60 Jahre hauptsächlich durch Isolierung aus dem grünen Knollenblätterpilz untersucht. Die Totalsynthese blieb jedoch wegen der einzigartigen Struktureigenschaften schwierig. ist ein potenter Inhibitor RNA‐Polymerase II. Unterbrechung dieses fundamentalen Transkriptionsprozesses von Eukaryonten führt unweigerlich zur Apoptose. Dieser einzigartige Mechanismus macht das Toxin zu einem idealen Kandidaten für Antikörper‐Toxin‐Konjugate...
Clofarabine lipids form superstructures <italic>via</italic> diastereoselective self-assembly.
Abstract Background: ATACs (antibody-targeted Amanitin conjugates) comprise a new class of antibody-drug conjugates using as toxic payload. binds to the eukaryotic RNA pol II and thereby inhibits cellular transcription process at very low concentrations. In current study, in vitro vivo data an ATAC targeting PSMA (prostate specific membrane antigen) are presented. is predominantly expressed on malignant prostate cells carcinoma correlates with tumor progression. Hence it considered...
Abstract Antitumoral activity of monoclonal antibodies can be dramatically enhanced by conjugation to toxic small molecules. Beside the recent approval Kadcyla (T-DM1) and Adcetris (SGN-35) more than 30 antibody-drug conjugates (ADC) have entered clinical trials, promising strengthen therapeutic capabilities for cancer treatment in next decade. Surprisingly most ADCs are based on one few compounds only an even smaller number toxicity mechanisms: Most coupled microtubuli-targeting auristatins...
Abstract Background ATACs (antibody-targeted Amanitin conjugates) comprise a new class of antibody-drug conjugates using amanitin as toxic payload. binds to the eukaryotic RNA pol II and thereby inhibits cellular transcription process at very low concentrations. In current study, in vitro vivo data targeting CD19 (also known B4, CVID3) are presented. CD19, I transmembrane glycoprotein with no significant homology any protein, is expressed B cells B-cell malignancies like acute lymphocytic...
Abstract Background: ATACs (Antibody Targeted Amanitin Conjugates) comprise a new class of antibody-drug conjugates using amanitin as toxic payload. binds to the eukaryotic RNA pol II and thereby inhibits cellular transcription process at very low concentrations. We accomplished chemical synthesis were able synthesize variants in order optimize toxin structure for different tumors antibodies. will present vitro vivo data eight linker-amanitin constructs attached three antibodies targeting...
Background: Triple negative breast cancer (TNBC) is the most difficult to treat subtype of with limited therapeutic options. At least 50% TNBC patients have low epidermal growth factor receptor 2 (HER2; ERBB2) expression majority harboring hemizygous loss POLR2A/chromosome 17p. For these treatment antibody-targeted amanitin conjugates (ATACs) targeting HER2 a new promising approach. ATACs comprise class antibody-drug (ADCs) using as toxic payload and are able kill antigen expressing cells....
<p>Supplementary Table and Figures</p>
<p>Supplementary Table and Figures</p>